EP0789021B1 - Hydroxamsäuren als Kappa-Opiat-Rezeptoragonisten - Google Patents

Hydroxamsäuren als Kappa-Opiat-Rezeptoragonisten Download PDF

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Publication number
EP0789021B1
EP0789021B1 EP97200003A EP97200003A EP0789021B1 EP 0789021 B1 EP0789021 B1 EP 0789021B1 EP 97200003 A EP97200003 A EP 97200003A EP 97200003 A EP97200003 A EP 97200003A EP 0789021 B1 EP0789021 B1 EP 0789021B1
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EP
European Patent Office
Prior art keywords
hydroxy
alkyl
phenyl
dichlorophenyl
acetamide
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Expired - Lifetime
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EP97200003A
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English (en)
French (fr)
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EP0789021A1 (de
Inventor
Fumitaka Ito
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Pfizer Inc
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Pfizer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • opioid analgesics such as morphine act as a ⁇ -receptor agonist
  • separating the action based on a ⁇ -receptor agonist from the action based on ⁇ -receptor agonist has been investigated.
  • the present invention provides a compound of the following formula: or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, C 2-4 alkenyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylthio-C 1-4 alkyl, halo-substituted C 1-4 alkyl or hydroxy-C 1-4 alkyl or R 1 and R 2 are taken together with the nitrogen to which they are attached and form a saturated or unsaturated 3-, 4-, 5-, 6- or 7- membered heterocyclic containing one to two heteroatoms, optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, halo (i.e., fluoro, chloro, bromo or iodo), benzyl, hydroxy, carboxy, cyano, nitro, di C 1-6 alkylamino, amino, C 1-6 alkylsu
  • X is phenyl substituted with up to three substituents selected from chloro, methyl and CF 3, preferably 3,4-dichlorophenyl; and R 3 is hydrogen.
  • Preferred individual compounds of the invention are:
  • the ⁇ agonists compounds of formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals.
  • these compounds are most desirably administered to humans in doses ranging from 0.01 mg to 50 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen.
  • a dosage level that is in the range of from 0.01 mg to 1 mg per kg of body weight per day, single or divided dosage is most desirably employed in humans for the treatment of pain in a postoperative patient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)

Claims (11)

  1. Verbindung der nachstehenden Formel
    Figure 00300001
       oder ein pharmazeutisch verträgliches Salz davon, worin
    R1 und R2 unabhängig voneinander Wasserstoff, C1-4-Alkyl, C3-7-Cycloalkyl, C2-4-Alkenyl, C1-4-Alkoxy-C1-4-alkyl, C1-4-Alkylthio-C2-4-alkyl, Halogen-substituiertes C1-4-Alkyl oder Hydroxy-C1-4-alkyl darstellen; oder R1 und R2 mit dem Stickstoffatom, an das sie gebunden sind, zusammengenommen einen ein bis zwei Heteroatome enthaltenden, gesättigten oder ungesättigten 3-, 4-, 5-, 6- oder 7-gliedrigen Heterocyclus bilden, der gegebenenfalls mit C1-6-Alkyl, C1-6-Alkoxy, C2-6-Alkenyl, Halogen (das heißt Fluor, Chlor, Brom oder Jod), Benzyl, Hydroxy, Carboxy, Cyano, Nitro, Di-C1-6-alkylamino, Amino, C1-6-Alkylsulfonylamino, Mercapto, C1-6-Alkylthio, C1-6-Alkylsulfinyl, C1-6-Alkylsulfonyl, Phenyl, Phenoxy und OY, worin Y eine Hydroxyschutzgruppe darstellt, substituiert ist, mit der Maßgabe, dass der Heterocyclus nicht Pyrrolidinyl ist;
    R3 Wasserstoff, C1-4-Alkyl oder eine Hydroxyschutzgruppe darstellt;
    Ar Phenyl, gegebenenfalls substituiert mit ein oder mehreren Substituenten, unabhängig ausgewählt aus Halogen, Hydroxy, C1-4-Alkyl, C1-4-Alkoxy, C1-4-Alkoxy-C1-4-alkyloxy, CF3 und Carboxy-C1-4-alkyloxy, darstellt; und
    X Phenyl, Naphthyl, Biphenyl, Indanyl, Benzofuranyl, Benzothiophenyl, 1-Tetralon-6-yl, C1-4-Alkylendioxy, Pyridyl, Furyl oder Thienyl darstellt, wobei diese Gruppen gegebenenfalls mit bis zu drei Substituenten, ausgewählt aus Halogen, C1-4-Alkyl, C1-4-Alkoxy, Hydroxy, NO2, CF3 und SO2CH3, substituiert sind.
  2. Verbindung nach Anspruch 1, worin R1 und R2 unabhängig voneinander C1-4-Alkyl oder Halogen-substituiertes C1-4-Alkyl darstellen; oder R1 und R2 zusammengenommen eine 5- oder 6-gliedrige cyclische Aminogruppe bilden, die gegebenenfalls mit ein bis drei Substituenten, ausgewählt aus Hydroxy, Halogen, C1-4-Alkyl oder -OY, worin Y eine Hydroxyschutzgruppe darstellt, substituiert sind.
  3. Verbindung nach Anspruch 2, worin Ar Phenyl darstellt.
  4. Verbindung nach Anspruch 3, worin X Phenyl, substituiert mit bis zu drei Substituenten, ausgewählt aus Chlor, Methyl und CF3, darstellt und R3 Wasserstoff darstellt.
  5. Verbindung nach Anspruch 4, worin X 3,4-Dichlorphenyl darstellt.
  6. Verbindung nach Anspruch 1, die eine der nachstehenden ist:
    2-(3,4-Dichlorphenyl)-N-hydroxy-N-(1-(S)-phenyl-2-piperidinoethyl)acetamid;
    2-(3,4-Dichlorphenyl) -N-hydroxy-N-[1-(S)-phenyl-2-(3-pyrrolidinoethyl)]acetamid;
    2-(3,4-Dichlorphenyl)-N-hydroxy-N-[1-(S)-phenyl-2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]acetamid;
    2- (3,4-Dichlorphenyl)-N-(2-N,N-dimethylamino-1-(S)-phenylethyl)-N-hydroxyacecamid;
    N-(2-Azetidinyl-1-(S)-phenylethyl)-N-hydroxy-2-(3,4-dichlorphenyl)acetamid;
    2-(3,4-Dichlorphenyl)-N-(2-hexamethylenimino-1-(S)-phenylethyl) -N-hydroxyacetamid;
    2-(2,3-Dichlorphenyl)-N-hydroxy-N-[1-(S)-phenyl-2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]acetamid;
    N-Hydroxy-N-[1-(S)-phenyl-2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]-2-(2,3,6-trichlorphenyl)acetamid; und
    2-(3,4-Dichlorphenyl)-N-[2-N'-(2-fluorethyl)-N'-methylamino-1-(S)-phenylethyl)-N-hydroxyacetamid.
  7. Verbindung nach Anspruch 1, die eine der nachstehenden ist:
    2-(3,4-Dichlorphenyl)-N-hydroxy-N-(1-(S)-phenyl-2-piperidinoethyl)acetamid;
    2-(3,4-Dichlorphenyl)-N-hydroxy-N-[1-(S)-phenyl-2-(3-pyrrolidinoethyl)]acetamid;
    2-(3,4-Dichlorphenyl)-N-hydroxy-N-[1-(S)-phenyl-2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]acetamid; und
    2- (3,4-Dichlorphenyl) -N- [2-N'- (2-fluorethyl) -N'-methylamino-1-(S)-phenylethyl]-N-hydroxyacetamid.
  8. Pharmazeutische Zusammensetzung, umfassend eine Verbindung der Formel (I) oder ein pharmazeutisch verträgliches Salz davon nach einem der Ansprüche 1 bis 7, zusammen mit einem pharmazeutisch verträglichen Verdünnungsmittel oder Träger.
  9. Verbindung der Formel (I) oder ein pharmazeutisch verträgliches Salz davon nach einem der Ansprüche 1 bis 7 oder eine pharmazeutische Zusammensetzung, die eine solche Einheit enthält, nach Anspruch 8, zur Verwendung als Arzneimittel.
  10. Verwendung einer Verbindung der Formel (I) oder eines pharmazeutisch verträglichen Salzes davon nach einem der Ansprüche 1 bis 7, zur Herstellung eines Arzneimittels zur Behandlung eines Zustands, für den Agonistenaktivität gegen einen opfolden Kapparezeptor benötigt wird.
  11. Verwendung einer Verbindung der Formel (I) oder eines pharmazeutisch verträglichen Salzes davon nach einem der Ansprüche 1 bis 7, zur Herstellung eines Arzneimittels, das als analgetisches, antientzündliches, diuretisches, hustenlinderndes, anästhetisches oder neuroprotektives Mittel wirksam ist oder für die Behandlung von Schlaganfall oder funktioneller Darmerkrankung.
EP97200003A 1996-02-07 1997-01-07 Hydroxamsäuren als Kappa-Opiat-Rezeptoragonisten Expired - Lifetime EP0789021B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PT97200003T PT789021E (pt) 1997-01-07 1997-01-07 Compostos de acido pirrolidinil hidroxamico e o processo para a sua producao

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IB9600099 1996-02-07
WOPCT/IB96/00099 1996-02-07

Publications (2)

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EP0789021A1 EP0789021A1 (de) 1997-08-13
EP0789021B1 true EP0789021B1 (de) 2000-10-11

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US (1) US5837717A (de)
EP (1) EP0789021B1 (de)
JP (1) JP3190588B2 (de)
AT (1) ATE196901T1 (de)
CA (1) CA2196845C (de)
DE (1) DE69703256T2 (de)
DK (1) DK0789021T3 (de)
ES (1) ES2151222T3 (de)
GR (1) GR3034923T3 (de)
MX (1) MX9701042A (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0982297A3 (de) * 1998-08-24 2001-08-01 Pfizer Products Inc. Verfahren zur Herstellung von Hydroxy-pyrrolidinyl Hydroxamsäure Derivaten, die kappa Opioid-Rezeptor Agonisten sind
US7160902B2 (en) 2003-11-14 2007-01-09 Adolor Corporation Amide derivatives and methods of their use

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8618188D0 (en) * 1986-07-25 1986-09-03 Ici Plc Diamine compounds
US5232978A (en) * 1988-12-23 1993-08-03 Merck Patent Gesellschaft Mit Beschrankter Haftung 1-(2-arylethyl)-pyrrolidines
DE4034785A1 (de) 1990-11-02 1992-05-07 Merck Patent Gmbh 1-(2-arylethyl)-pyrrolidine
JPH0730061B2 (ja) * 1991-02-07 1995-04-05 ファイザー製薬株式会社 ヒドロキサム酸誘導体および組成物
US5132319A (en) * 1991-03-28 1992-07-21 Merck Frosst Canada, Inc. 1-(hydroxylaminoalkyl) indole derivatives as inhibitors of leukotriene biosynthesis
US5128364A (en) * 1991-03-28 1992-07-07 Merck Frosst Canada, Inc. Pyrrolo[1,2-a]indole hydroxylamine derivatives as inhibitors of leukotriene biosynthesis
US5234933A (en) * 1991-10-31 1993-08-10 Board Of Governors Of Wayne State University And Vanderbilt University Cyclic hydroxamic acids
IL117440A0 (en) * 1995-03-31 1996-07-23 Pfizer Pyrrolidinyl hydroxamic acid compounds and their production process

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Publication number Publication date
ATE196901T1 (de) 2000-10-15
DK0789021T3 (da) 2000-11-13
CA2196845C (en) 2001-08-21
CA2196845A1 (en) 1997-08-08
US5837717A (en) 1998-11-17
DE69703256T2 (de) 2001-02-22
JPH11180950A (ja) 1999-07-06
JP3190588B2 (ja) 2001-07-23
EP0789021A1 (de) 1997-08-13
DE69703256D1 (de) 2000-11-16
ES2151222T3 (es) 2000-12-16
MX9701042A (es) 1998-05-31
GR3034923T3 (en) 2001-02-28

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